ABSTRACT Current treatments for obesity have been largely unsuccessful in maintaining long-term weight loss, demonstrating the tremendous need for new insight into mechanisms that may stably alter body mass and composition. There is significant heterogeneity in response to intervention/prevention programs designed to reduce the risk and occurrence of obesity, suggesting that some individuals may be responsive to a given intervention while others are not. In this project, we will integrate dietary, psychosocial/behavioral, exercise performance, and metabolomics data, within the context of a well-controlled exercise intervention, to characterize the behavioral phenomics of energy balance (BPEB). BPEB is a high dimensional representation of the complex interplay between behavioral components of energy balance characterized at multiple levels, from dietary intake to exercise and physical activity to the psychosocial drivers of both behaviors. In addition, we will determine how exercise training influences change in BPEB, and we will use high density genotype and metabolomic data to derive the genetic and metabolic pathways that interact with BPEB to regulate and influence changes in body mass/composition following a high intensity aerobic exercise intervention. In this proposal, we will leverage the existing resources of the Training Interventions and Genetics of Exercise Response (TIGER) Study and the UK Biobank. The TIGER Study is one of the largest studies of the genetics of exercise response in which participants have undergone a rigorous and empirically-documented aerobic exercise training protocol. The TIGER Study cohort consists of 3,665 participants from multiple racial/ethnic groups, with an average BMI of 26.2?6.3 kg/m2 . A comprehensive battery of behavioral data, phenotypes, genotypes, and stored samples (DNA, RNA, and plasma) are available to this proposed study, and more than 120,000 recorded exercise sessions with documented duration, intensity, and mode have been recorded in the TIGER Study. Participants also reported psychological parameters related to eating behavior and physical activity. Importantly, a substantial proportion of TIGER participants experienced significant weight loss throughout the course of the study, despite the fact that TIGER was not a weight loss trial, providing a unique opportunity to study spontaneous changes in dietary and psychosocial factors in the context of exercise. We will use the resources of the UK Biobank, which has more than 500,000 participants and a complementary array of phenotype and behavior data, for validation of our findings. Our goal is to reveal new pathways that regulate, influence, and/or interact with diet and exercise behavior to ultimately determine body mass and adiposity.